A great deal of evidence supports the hypothesis that selective targeting of Abeta42 may be an ideal therapeutic strategy to prevent and possibly treat Alzheimer's disease (AD), the major cause of dementia among the elderly. We have previously reported that select NSAIDS were capable of selectively modulating Abeta42. More recently, we have found that numerous compounds increase Abeta42. Abeta42 modulating agents (generically referred to as gamma-secretase modulators or GSMs) minimally alter total Abeta production but shift the gamma-secretase cleavage site. Abeta42 lowering GSMs increase the production of shorter Abeta peptides and raising agents decrease the levels of shorter Abeta peptides. Current data using novel photoaffinity ligands that modulate Abeta42 cleavage indicate that Abeta42 modulating agents alter production and aggregation of Abeta by binding to a site within the Abeta region of APP carboxyl terminal fragments (CTFs). We hypothesize that binding of the Abeta region of APP CTFs alters the conformation of the APP CTF or its position in the membrane resulting in altered gamma-secretase cleavage, and following cleavage compound binding alters Abeta aggregation. We outline a number of studies to extend our current data that support this hypothesis. We will also evaluate the linked hypotheses regarding the in vivo mechanism of action of Abeta42 lowering NSAIDs and other Abeta42 altering agents. We will perform chronic dosing studies with drug-like Abeta42 lowering and raising agents in APP and BRI-Abeta42 mouse models to evaluate the relative contribution of altering Abeta42 production vs. altering aggregation with respect to effect on Abeta loads and other AD-like pathologies. We will also determine if elevations in shorter Abeta peptides are protective. For these later studies we will use recombinant adenoassociated virus (rAAV) to deliver BRI-Abeta fusion constructs encoding Abeta 1-34, 1-37, and 1-38 to the brain of neonatal APP mice. This methodology creates "somatic brain transgenics" and will allow us to rapidly evaluate the effects of shorter Abeta peptides on Abeta deposition. Effects on Abeta deposition and synaptic transmission will be evaluated. The influence of shorter Abeta peptides on Abeta42 aggregation in vitro will also be evaluated in vitro. These studies should provide additional insight into the mechanisms whereby Abeta42 modulating agents shift Abeta cleavage and how they exert their protective effects in vivo. PUBLIC HEALTH RELEVANCE: A great deal of evidence supports the hypothesis that selective targeting of Abeta42 may be an ideal therapeutic strategy to prevent and possibly treat Alzheimer's disease (AD), the major cause of dementia among the elderly. The proposed studies should provide additional insight into the mechanisms whereby Abeta42 modulating agents shift Abeta cleavage and how they exert their protective effects in vivo. These studies will thereby inform future therapeutic development of this class of potential AD therapeutics. [unreadable] [unreadable] [unreadable]